This project seeks to understand the physiology and pathophysiology of ovarian follicle development and function, and to thereby develop clinical diagnostic and therapeutic applications for women with ovulatory disorders. During this period we have focused on premature ovarian failure, a condition which prematurely terminates fertility in 1% of women. We have particular interest in autoimmune-mediated ovarian failure and seek to improve our understanding of this condition through clinical research and through basic immunologic research employing a mouse model of autoimmune ovarian failure (induced by neonatal thymectomy). During this period we have demonstrated that during a 4 month observation period with serial serum estradiol measurements we can detect ovarian follicle function in approximately 50% of patients with premature ovarian failure. Furthermore, almost 20% of these patients ovulated during this observation as determined by serial progesterone levels. We completed a controlled evaluation of gonadotropin suppression as a means to induce remission in patients with ovarian failure. We demonstrated that four months of gonadotropin suppression with a gonadotropin releasing hormone agonist was no more effective than placebo in inducing return of ovarian function. During the current year we have continued our work in a mouse model of autoimmune lymphocytic oophoritis. We are defining the time course and histologic location of the ovarian lymphocytic infiltrate. We have developed and validated a technique to localize mouse lymphocytes in the ovary by using immunohistochemistry and a monoclonal antibody against a surface protein specific to mouse lymphocytes (CD45). We plan to continue to define the pathogenesis of autoimmune ovarian failure in the neonatally thymectomized mouse by using immunohistochemical techniques to characterize the initial events in this process, and by using cell culture techniques to assess T lymphocyte proliferation in response to ovarian antigens. In the coming years we also plan to evaluate other treatments for premature ovarian failure by controlled prospective clinical trials and to assess the pathophysiologic role of immunoglobulins and T lymphocytes in autoimmune premature ovarian failure.